Stereodivergent, Multicomponent Metal-Catalyzed Couplings Generating Three Stereocenters: Combining Enantioselective Rh-Catalyzed Conjugate Addition and Ir-Catalyzed Allylic Alkylation

Stereodivergent dual catalysis has emerged as a powerful tool to selectively prepare all four stereoisomers in molecules containing two chiral centers from common starting materials. Most processes involve the use of two substrates, and it remains challenging to use dual catalyst approaches to generate molecules having three newly formed stereocenters with high diastereo- and enantioselectivity. Here we report a multicomponent, stereodivergent method for the synthesis of targets containing three contiguous stereocenters by the combination of enantioselective Rh-catalyzed conjugate addition and Ir-catalyzed allylic alkylation methodologies. Both cyclic and acyclic ,-unsaturated ketones undergo -arylation using aryl boron reagents to form an enolate nucleophile that can be subsequently allylated at the -position. The reactions proceed with generally >95% ee and with >90:10 dr. Epimerization at the -carbonyl center enables the preparation of any of the eight possible stereoisomers from common starting materials, as demonstrated for cyclohexanone products

Catalytic Oxidative Benzylation of Amines Enabled by Direct Ionic Decarboxylation

We report a method for the decarboxylative alkylation of amines via the direct generation of a benzylic nucleophiles

Direct Reversible Decarboxylation from Stable Organic Acids in Solution

Many classical and emerging methodologies in organic chemistry rely on carbon dioxide extrusion to generate reactive intermediates for subsequent bond-­forming events. Synthetic reactions that involve the microscopic reverse, the carboxylation of reactive intermediates such as organometallic nucleophiles, occur under vastly different reaction conditions. We found that under appropriate conditions chemically stable C(sp3) carboxylates undergo rapid, uncatalyzed reversible decarboxylation in solution. The decarboxylation/carboxylation process occurs through the generation and trapping of otherwise undetectable carbanion intermediates that are largely resistant to protodecarboxylation in the presence of Brønsted acids or to trapping by external electrophiles. Isotopically labelled carboxylic acids, including drug molecules and valuable synthetic intermediates, can be prepared in high chemical and isotopic yield by simply supplying an atmosphere of 13CO2 to carboxylate salts in polar aprotic solvents. Our results indicate that the reversibility of decarboxylation from organic acids should be taken into consideration when designing and executing decarboxylative functionalization processes

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

Carbazole/cyanobenzene photocatalysts promote the direct isotopic carboxylate exchange of C(sp3 )-acids with labelled CO2. Substrates that are not compatible with transition metal catalyzed degradation-reconstruction approaches or prone to thermally induced reversible decarboxylation undergo isotopic incorporation at room temperature in short reaction times. The radiolabelling of drug molecules and precursors with [11C]CO2 is demonstrated

Rh-Catalyzed Asymmetric Hydrogenation of 1,2-Dicyanoalkenes

A highly efficient enantioselective hydrogenation of 1,2-dicyanoalkenes catalyzed by the complex of rhodium and f-spiroPhos has been developed. A series of 1,2-dicyanoalkenes were successfully hydrogenated to the corresponding chiral 1,2-dicyanoalkanes under mild conditions with excellent enantioselectivities (up to 98% ee). This methodology provides efficient access to the asymmetric synthesis of chiral diamines

Site-Selective Hydrogenation of Electron-Poor Alkenes and Dienes Enabled by a Rh-Catalyzed Hydride Addition/Protonolysis Mechanism

The transition metal catalyzed hydrogenation of alkenes is a well-developed technology used on a lab scale as well as on large scales in the chemical industry. Site- and chemoselective mono-hydrogenations of polarized conjugated dienes remain challenging. Instead, stoichiometric main-group hydrides are used rather than H2. As part of an effort to develop a scalable route to prepare geranylacetone, we discovered that Rh(CO)2acac/xantphos based catalysts enable the selective monohydrogenation of electron-poor 1,3-dienes, enones, and other polyunsaturated substrates. D-labeling and DFT studies support a mechanism where a nucleophilic Rh(I)-hydride selectively adds to electron-poor alkenes and the resulting Rh-enolate undergoes subsequent inner-sphere protonation by alcohol solvent. The finding that (Ln)Rh(H)(CO) type catalysts can enable selective mono-hydrogenation of electron-poor (poly)enes provides a valuable tool in the design of related chemoselective reduction processes of unsaturated substrates

Enantioselective Hydrogenation of β,β-Disubstituted Unsaturated Carboxylic Acids under Base-Free Conditions

An additive-free enantioselective hydrogenation of β,β-disubstituted unsaturated carboxylic acids catalyzed by the Rh–(<i>R</i>,<i>R</i>)-f-spiroPhos complex has been developed. Under mild conditions, a wide scope of β,β-disubstituted unsaturated carboxylic acids were hydrogenated to the corresponding chiral carboxylic acids with excellent enantioselectivities (up to 99.3% ee). This methodology was also successfully applied to the synthesis of the pharmaceutical molecule indatraline

Enantioselective Synthesis of Boryl Tetrahydroquinolines via Cu-Catalyzed Hydroboration

A Cu-catalyzed regio- and enantioselective hydroboration of 1,2-dihydroquinolines with high yields and excellent enantioselectivities (up to 98% ee) was presented. This method could be applied in the asymmetric synthesis of the important intermediates used in the enantioselective synthesis of the potential agent Sumanirole for the treatment of Parkinson’s disease and of the potentially interesting positive inotropic agent (<i>S</i>)-<b>903</b>

Highly Efficient Rh-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated Nitriles

A highly efficient enantioselective hydrogenation of α,β-unsaturated nitriles catalyzed by Rh-(<i>R</i>,<i>R</i>)-f-spiroPhos complex has been developed. With Rh-(<i>R</i>,<i>R</i>)-f-spiroPhos catalyst and under mild conditions, a wide range of α,β-unsaturated nitriles including the (<i>E</i>)- and (<i>Z</i>)-isomers of 3-alkyl-3-aryl, 3,3-diaryl, and 3,3-dialkyl α,β-unsaturated nitriles were hydrogenated to the corresponding chiral nitriles with excellent enantioselectivities (up to 99.9% ee) and high turnover numbers (TON up to 10,000)

Asymmetric Hydrogenation of β‑Aryloxy/Alkoxy Cinnamic Nitriles and Esters

A highly efficient and enantioselective hydrogenation of β-aryloxy/alkoxy cinnamic nitriles and esters under mild conditions has been realized by using a rhodium catalyst with a chiral f-spiroPhos ligand. The method provides efficient access to the asymmetric synthesis of a variety of chiral β-oxy-functionalized nitriles and esters with excellent enantioselectivities (up to 99.9% ee) and high turnover numbers (TON of up to 50000). This methodology has also been successfully applied to the concise and practical synthesis of the chiral pharmaceutical nisoxetine